Binge ethanol exposure during adolescence leads to a persistent loss of neurogenesis in the dorsal and ventral hippocampus that is associated with impaired adult cognitive functioning.

Vetreno RP, Crews FT - Front Neurosci (2015)

Bottom Line:
This reduction in neurogenesis was accompanied by a concomitant reduction in proliferating cells (Ki-67) and an increase in cell death (cleaved caspase-3).In the hippocampus, AIE treatment induced a long-term upregulation of neuroimmune genes, including Toll-like receptor 4 (TLR4) and its endogenous agonist high-mobility group box 1 as well as several proinflammatory signaling molecules.Interestingly, object recognition memory was positively correlated with DCX + IR in both the dorsal and ventral hippocampal dentate gyrus while latency to enter the center of the apparatus was negatively correlated with DCX + IR in the ventral dentate gyrus.

Affiliation: Department of Psychiatry, Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina Chapel Hill, NC, USA.

ABSTRACTAdolescence is a developmental period that coincides with the maturation of adult cognitive faculties. Binge drinking is common during adolescence and can impact brain maturation. Using a rodent model of adolescent intermittent ethanol (AIE; 5.0 g/kg, i.g., 20% EtOH w/v; 2 days on/2 days off from postnatal day [P]25 to P55), we discovered that AIE treatment reduced neurogenesis (i.e., doublecortin-immunoreactive [DCX + IR] cells) in both the dorsal and ventral hippocampal dentate gyrus of late adolescent (P56) male Wistar rats that persisted during abstinence into adulthood (P220). This reduction in neurogenesis was accompanied by a concomitant reduction in proliferating cells (Ki-67) and an increase in cell death (cleaved caspase-3). In the hippocampus, AIE treatment induced a long-term upregulation of neuroimmune genes, including Toll-like receptor 4 (TLR4) and its endogenous agonist high-mobility group box 1 as well as several proinflammatory signaling molecules. Administration of lipopolysaccharide, a gram-negative endotoxin agonist at TLR4, to young adult rats (P70) produced a similar reduction of DCX + IR cells that was observed in AIE-treated animals. Behaviorally, AIE treatment impaired object recognition on the novel object recognition task when assessed from P163 to P165. Interestingly, object recognition memory was positively correlated with DCX + IR in both the dorsal and ventral hippocampal dentate gyrus while latency to enter the center of the apparatus was negatively correlated with DCX + IR in the ventral dentate gyrus. Together, these data reveal that adolescent binge ethanol exposure persistently inhibits neurogenesis throughout the hippocampus, possibly through neuroimmune mechanisms, which might contribute to altered adult cognitive and emotive function.

Mentions:
Since AIE treatment leads to persistent changes in hippocampal neurogenesis and neurogenesis is implicated in object recognition memory (Jessberger et al., 2009; Suarez-Pereira et al., 2015), we correlated the discrimination ratio obtained from the NOR test in the P220 subject group with expression of DCX in the dorsal and ventral hippocampal dentate gyrus of adult rats (P220). As depicted in Figure 7, the discrimination ratio was positively correlated with DCX + IR in both the dorsal (r = 0.64, N = 14, p < 0.05) and ventral (r = 0.68, N = 14, p < 0.01) hippocampal dentate gyrus of adult rats (P220). Given the involvement of the ventral hippocampus in anxiety-like behavior (McHugh et al., 2004), we next assessed the association between latency to enter the center of the open-field during the habituation phase, and expression of DCX in the dorsal and ventral hippocampal dentate gyrus of adult rats (P220). We found that DCX + IR in the ventral, but not dorsal, hippocampal dentate gyrus was negatively correlated with latency to enter the center of the apparatus (r = –0.54, p < 0.05, N = 14). Thus, hippocampal neurogenesis is correlated with both novel object recognition memory and anxiety-like behavior in the adult rats.

Mentions:
Since AIE treatment leads to persistent changes in hippocampal neurogenesis and neurogenesis is implicated in object recognition memory (Jessberger et al., 2009; Suarez-Pereira et al., 2015), we correlated the discrimination ratio obtained from the NOR test in the P220 subject group with expression of DCX in the dorsal and ventral hippocampal dentate gyrus of adult rats (P220). As depicted in Figure 7, the discrimination ratio was positively correlated with DCX + IR in both the dorsal (r = 0.64, N = 14, p < 0.05) and ventral (r = 0.68, N = 14, p < 0.01) hippocampal dentate gyrus of adult rats (P220). Given the involvement of the ventral hippocampus in anxiety-like behavior (McHugh et al., 2004), we next assessed the association between latency to enter the center of the open-field during the habituation phase, and expression of DCX in the dorsal and ventral hippocampal dentate gyrus of adult rats (P220). We found that DCX + IR in the ventral, but not dorsal, hippocampal dentate gyrus was negatively correlated with latency to enter the center of the apparatus (r = –0.54, p < 0.05, N = 14). Thus, hippocampal neurogenesis is correlated with both novel object recognition memory and anxiety-like behavior in the adult rats.

Bottom Line:
This reduction in neurogenesis was accompanied by a concomitant reduction in proliferating cells (Ki-67) and an increase in cell death (cleaved caspase-3).In the hippocampus, AIE treatment induced a long-term upregulation of neuroimmune genes, including Toll-like receptor 4 (TLR4) and its endogenous agonist high-mobility group box 1 as well as several proinflammatory signaling molecules.Interestingly, object recognition memory was positively correlated with DCX + IR in both the dorsal and ventral hippocampal dentate gyrus while latency to enter the center of the apparatus was negatively correlated with DCX + IR in the ventral dentate gyrus.

Affiliation:
Department of Psychiatry, Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina Chapel Hill, NC, USA.

ABSTRACTAdolescence is a developmental period that coincides with the maturation of adult cognitive faculties. Binge drinking is common during adolescence and can impact brain maturation. Using a rodent model of adolescent intermittent ethanol (AIE; 5.0 g/kg, i.g., 20% EtOH w/v; 2 days on/2 days off from postnatal day [P]25 to P55), we discovered that AIE treatment reduced neurogenesis (i.e., doublecortin-immunoreactive [DCX + IR] cells) in both the dorsal and ventral hippocampal dentate gyrus of late adolescent (P56) male Wistar rats that persisted during abstinence into adulthood (P220). This reduction in neurogenesis was accompanied by a concomitant reduction in proliferating cells (Ki-67) and an increase in cell death (cleaved caspase-3). In the hippocampus, AIE treatment induced a long-term upregulation of neuroimmune genes, including Toll-like receptor 4 (TLR4) and its endogenous agonist high-mobility group box 1 as well as several proinflammatory signaling molecules. Administration of lipopolysaccharide, a gram-negative endotoxin agonist at TLR4, to young adult rats (P70) produced a similar reduction of DCX + IR cells that was observed in AIE-treated animals. Behaviorally, AIE treatment impaired object recognition on the novel object recognition task when assessed from P163 to P165. Interestingly, object recognition memory was positively correlated with DCX + IR in both the dorsal and ventral hippocampal dentate gyrus while latency to enter the center of the apparatus was negatively correlated with DCX + IR in the ventral dentate gyrus. Together, these data reveal that adolescent binge ethanol exposure persistently inhibits neurogenesis throughout the hippocampus, possibly through neuroimmune mechanisms, which might contribute to altered adult cognitive and emotive function.